Spraying device with improved tip and method of manufacture

ABSTRACT

The invention provides a precision spraying device having an improved atomizing end for reproducibly forming droplets from small amounts of liquid with improved operational stability and spray pattern quality as well as a method of manufacturing. The invention further provides a method for reproducibly coating substrates using the spraying device of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application relates to and claims priority from commonly owned U.S.patent Application Ser. No. 11/545,282, filed on Oct. 10, 2006 and is acontinuation-in-part of U.S. patent application Ser. No. 11/408,421,filed on Apr. 21, 2006.

FEDERALLY SPONSORED RESEARCH

Not Applicable

SEQUENCE LISTING OR PROGRAM

Not Applicable

TECHNICAL FIELD

The present invention relates to improved multiple fluid sprayingdevices for the controlled atomization of small liquid amounts and amethod for providing a repeatable spray performance in terms of dropletsize and spatial droplet distribution. The invention is particularlysuitable for drug delivery applications, such as for the production ofcoated medical implants in which batch to batch reproducibility iscrucial.

BACKGROUND OF THE INVENTION

In pharmaceutical and biomedical applications, including drug coating ofmedical devices, tablet coating, oral drug delivery, and tissueengineering there is a trend to use multiple fluid spraying devices toatomize liquid compositions typically comprising one or more therapeuticsubstances as well as components used to modulate drug release kinetics,to stabilize a drug and/or to increase drug solubility. For example,medical devices including stents, vascular grafts, catheters, and thelike are typically coated using multiple fluid spraying devices todeliver a therapeutic substance to a lumen that reduces smooth muscletissue proliferation. The reproducible and homogeneous distribution ofthe therapeutic substance depends mainly on the performance of thespraying device in terms of droplet size and droplet size distribution,which, in turn, is crucial for the success of the particular drugdelivery application.

A typical multiple fluid spraying device is adapted to externallyatomize small liquid amounts in the order of 0.1 to 100 ml/h by acompressible fluid. It comprises a body having at least a liquid orificeand a tip defining a space for receiving the compressible fluid andhaving a central orifice for discharging the compressible fluid throughan annular gap formed between the liquid orifice and the body for thecompressible gas.

However, spraying devices known by the prior art have several drawbacks.Common problems associated with conventional spraying devices areimperfections of the orifices in terms of roundness and surface qualitydue to spiral marks and burrs that may require secondary procedures suchas electropolishing which, in turn, may result in manufacturingtolerance variations and/or out-of-roundness of the orifice. Inaddition, an inhomogeneous width of the gas annulus will have a negativeimpact on the spray quality. Thus, any imperfection and eccentricitybetween the axes of the liquid orifice and the tip can cause the flow ofthe atomizing gas to be cylindrically asymmetric with respect to theaxis of the liquid exiting from the liquid orifice and will lead tonebulization of the liquid composition by the atomizing gas that isdifferent on different sides of the spray plume.

Despite stringent quality control of the surface quality andconcentricity of liquid and gas orifices, the spray performance ofconventional spraying devices for the fine atomization of small liquidamounts remains generally poor.

Consequently, devices, even of the same type, will have different spraycharacteristics and poor spray quality and/or stability despite ofoptimum roundness and concentricity of the liquid and gas orifices. Poorreproducibility, especially from one spraying device to the next, is acommon problem in the production of coated medical implants, since poorspray stability and droplets that are too large and polydisperse in sizemay lead to an inhomogeneous distribution of the therapeutic substancewithin the coating, which may, in turn, have a negative impact on theperformance of the medical implants.

OBJECT OF THE INVENTION

Accordingly, there is a need for an improved spraying device todisintegrate small liquid amounts into fine droplets that overcomes theaforementioned problems with the prior art and improves the stabilityand performance of precision spraying processes such as medical stentcoating.

One object is to provide a spraying device that provides a homogeneousspatial droplet distribution, a tight droplet size distribution and aconsistent spray performance over time.

Another object is to provide a spraying device to atomize small liquidamounts that can be manufactured reproducibly resulting in a repeatableperformance from one spraying device to the next.

Yet another object is to provide a reproducible and precisemanufacturing method for machining the atomizing end of the sprayingdevice.

A further object is to provide a method to apply a homogeneous coatingon a medical device using the spraying device of the present invention.

Still another object is to provide a method to apply a homogeneous andreproducible coating on multiple medical devices using a plurality ofspraying device of the present invention.

These and additional features and advantages of the invention will bemore readily apparent upon reading the following description ofexemplary embodiment of the invention and upon reference to theaccompanying drawings herein.

SUMMARY OF THE INVENTION

In one embodiment, a device to disintegrate a liquid into fine dropletsusing an atomizing gas comprising a body having at least a liquidconduit extending from a liquid inlet to a liquid orifice and a tipdefining a space for receiving the atomizing gas and having an innertapered section extending to an orifice is provide. The tip isessentially coaxial with the body and an annular gap through which theatomizing gas is expelled is formed between the body and the orifice ofthe tip and at least the orifice of the tip and a portion of the innertapered section of the tip are machined to minimize the error ofconcentricity therebetween so that during operation a gas stream with asubstantially uniform gas velocity distribution about the perimeter ofthe annular gap is formed. In one or more embodiments, the orifice ofthe tip has a diameter of less than 1.2 mm and the error ofconcentricity between the orifice and said portion of the inner taperedsection is less than 20 microns. At least a portion of the inner sectionof the tip may be machined in the same setup as the orifice of the tip.The tip is preferably machined by a turning operation. The spayingdevice can further comprise a centering section, which may be machinedin the same setting as the orifice of the tip, wherein the centeringsection is used to align the tip in relation to the body and the errorof concentricity between the orifice of the tip and the centeringsection is smaller than 20 microns. The liquid conduit of the sprayingdevice may be free of constrictions and preferably consists of acapillary. Furthermore, the spraying device may comprise a second liquidinlet extending to a second liquid orifice surrounding and beingessentially coaxial with the first liquid orifice to separately supply asecond liquid, wherein the second liquid is disintegrated by theatomizing gas upon exiting the second liquid orifice and mixed with thefirst liquid. The device may also comprise electrostatic means toatomize the liquid.

In another embodiment, a method for manufacturing the tip of a sprayingdevice having a body with a liquid conduit extending from a liquid inletto a liquid orifice and a tip being essentially coaxial with the bodyand defining a space for receiving a fluid, the tip having a section foraligning the tip in relation to the body and an inner tapered sectionextending to an orifice for discharging the fluid, is provided. Themethod comprises the steps of machining the orifice of the tip and atleast a portion of the inner tapered section of the tip in the samesetup so that the error of concentricity therebetween is minimized.

In one or more embodiments, the step of machining the section foraligning the tip so that the error of concentricity between the orificeof the tip and the section for aligning the tip is smaller than 20microns is also provided. The orifice of the tip and the section foraligning the tip are preferably machined in the same setup.

In still another embodiment, a method for manufacturing the tip of aspraying device having a body with a liquid conduit extending from aliquid inlet to a liquid orifice and a tip being essentially coaxialwith the body and defining a space for receiving a fluid, the tip havinga section for aligning the tip in relation to the body and a innertapered section extending to an orifice with a diameter of less than 1.2mm for discharging the fluid, is provided. The method comprises thesteps of machining the inner tapered section of the tip and at least aportion of the tip in the same setup, clamping the tip on said machinedportion and machining the orifice of the tip by a turning operation sothat the error of concentricity between the orifice of the tip and theinner tapered section of the tip is minimized.

In yet another embodiment, a method to apply a coating to a medicaldevice using a spraying device having a body with a liquid conduitextending from a liquid inlet to a liquid orifice and a tip beingessentially coaxial with the body and defining a space for receiving anatomizing gas, the tip having an inner section extending to an orificewith a diameter of less than 1.2 mm for discharging the atomizing gasthrough an annular gap formed between the body and the orifice of thetip, is provided. The method includes the steps of feeding a liquid intothe liquid conduit and feeding a gas into the gas conduit and forming agas stream having a substantially uniform gas velocity distributionabout the perimeter of the annular gap, disintegrating the liquid intofine droplets through the momentum of the gas emerging from the annulargap, directing the droplets within the gas stream to the medical deviceso that the droplet trajectories are uniformly distributed around theextended longitudinal axis of the spraying device, and forming a coatingon the medical device.

In one or more embodiments, the error of concentricity between the innersection of the tip and the orifice of the tip is less than 20 microns.The volume median diameter of the generated droplets is preferably lessthan 10 microns. Also, the liquid flow may be directed at asubstantially constant velocity from the liquid inlet to the liquidorifice. The droplet size variation produced by the spraying device ispreferably less than 1%. The liquid can comprise a therapeutic substanceand/or a polymeric component. In addition, the step of feeding a secondliquid through an additional orifice positioned between the first liquidorifice and the orifice for the atomizing gas and disintegrating andmixing the second liquid with the first liquid through the momentum ofthe atomizing gas emerging from the annular gap may be provided.

In still another embodiment, a method to form a reproducible coating onmultiple stents using multiple spraying devices is provided. The methodincludes the steps of providing multiple stents, providing multiplespraying devices having a body with at least a liquid orifice and a tipbeing essentially coaxial with the body and defining a space forreceiving an atomizing gas, the tip having an inner section extending toan orifice for discharging the atomizing gas through an annular gapformed between the body and the orifice of the tip, feeding a liquidinto each spraying device and feeding a gas into each spraying deviceand forming a gas stream with a substantially uniform gas velocitydistribution about the perimeter of the annular gap, disintegrating theliquid into fine droplets through the momentum of the gas emerging fromthe annular gap so that the variation of the volume median diameter ofthe sprays produced by the separate spraying devices is less than 2%,directing the droplets within the gas streams to the medical devices sothat the droplet trajectories are uniformly distributed around theextended longitudinal axis of the spraying device, and forming a coatingon the stents.

In one or more embodiments, the orifice of the tip has a diameter ofless than 1.2 mm and the error of concentricity between the innersection of the tip and the orifice of the tip is less than 20 microns.Also, the error of concentricity between the inner section and theorifice of the tip is preferably less than 1.7% of the orifice diameterof the tip.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, serve to explain the principles of theinvention. The drawings are in simplified form and not to precise scale.In the drawings:

FIG. 1A is a longitudinal cross-sectional view of the spraying device ofthe present invention;

FIG. 1B is an expanded view of the atomizing end of the spraying deviceof FIG. 1A;

FIG. 2A is a longitudinal cross-sectional view of an alternativeembodiment of the spraying device;

FIG. 2B is an expanded view of the spraying device of FIG. 2A;

FIG. 3A shows the machining operation of the tip of the spraying deviceof the present invention;

FIG. 3B is a expanded view of the tip region shown in FIG. 3A;

FIG. 4 is a longitudinal cross-sectional detail view of the tip of aspraying device;

FIG. 5 is a CFD simulation of the velocity distribution of the atomizinggas within the annular gap of a spraying device;

FIG. 6 is a droplet size distribution comparison (Invention vs. PriorArt);

FIG. 7 is a comparison of the coefficient of variation (Invention vs.Prior Art);

FIG. 8 shows droplet size distributions of various individual sprayingdevices (Prior Art);

FIG. 9 shows droplet size distributions of various individual sprayingdevices;

FIG. 10 is a comparison of the coefficient of variation of ten nozzles(Invention vs. Prior Art);

FIG. 11 is a CFD simulation of a stent coating process (Prior Art); and

FIG. 12 is a CFD simulation of a stent coating process (Invention).

DETAILED DESCRIPTION OF THE INVENTION

The method and apparatus of the present invention were developed inresponse to the specific problems encountered with various apparatus fordisintegration of small liquid amounts into fine droplets to producecoated medical implants. Examples of such medical implants include heartvalves, pacemakers, tissues, sensors, catheters, needle injectioncatheters, blood clot filters, vascular grafts, stent grafts, biliarystents, colonic stents, bronchial/pulmonary stents, esophageal stents,ureteral stents, aneurysm filling coils, and other coil devices.

Use of the spray coating system model is not intended to limit theapplicability of the method to that field. It is anticipated that theinvention can be successfully utilized in other circumstances such as inthe field of inhalation formulation and in-vitro diagnostics.

The present invention comprises an improved spraying device and methodfor reproducibly atomizing small liquid amounts into fine dropletshaving a uniform droplet size distribution that are preferably appliedto medical devices to form a coating. The invention is directed toenhance medical implant coating processes in terms of coating qualityand reproducibility by providing an improved spraying device, amanufacturing method and quality criteria that ensure a consistent sprayperformance of a plurality of spraying devices of the same series usedin a medical implant production process.

When coating medial implants, the liquid to be atomized may be suppliedthrough one or more orifices and disintegrated using an atomizing gas.The liquid or liquid composition may comprise one or more film-formingagents, such as polymers, oils and/or fats, one or more solvents, andtherapeutic substances. The composition can also include beneficialagents, plastizers, buffers to adjust the pH of the composition,surfactants to enhance wettability of poorly soluble or hydrophobicmaterials, stabilizers, radiopaque elements, and radioactive isotopes.

The therapeutic substance may include, but is not limited to proteins,hormones, vitamins, anti-microbacterial agents, antioxidants, DNA,antimetabolite agents, anti-inflammatory agents, anti-restenosis agents,anti-thrombogenic agents, antibiotics, anti-platelet agents,anti-clotting agents, chelating agents, or antibodies. Specific examplesinclude hyaluronic acid (HA), Omega-3 fatty acids (DHA/EPA),Acetylsalicylic acid, Dexamethasone, M-prednisole, Interferon y-1b,Leflunomide, sirolimus, tacrolimus, everolimus, mizoribine, ABT-578,QP-2, Paclitaxel, actinomycin, methothrexate, angiopeptin, vincristine,mitomycine, statins, PCNA Ribozyne, Batimastat, Prolyl hydroxylaseinhibitors, C-proteinase inhibitors, Probucol, Re-Endothelialization,BCP671, VEGF Estradiols, NO donors, EPC antibodies; antioxidants such asprobucol and retinoic acid; angiogenic and anti-angiogenic agents;agents blocking smooth muscle cell proliferation such as rapamycin,angiopeptin, and monoclonal antibodies capable of blocking smooth musclecell proliferation; anti-inflammatory agents such as dexamethasone,prednisolone, corticosterone, budesonide, estrogen, sulfasalazine,acetyl salicylic acid, and mesalamine, lipoxygenase inhibitors; calciumentry blockers such as verapamil, diltiazem and nifedipine;antineoplastic/antiproliferative agents such as paclitaxel,methotrexate, doxorubicin, daunorubicin, cyclosporine, cisplatin,vinblastine, vincristine, colchicine, epothilones, endostatin,angiostatin, Squalamine, and thymidine kinase inhibitors; L-arginine;antimicrobials such as triclosan, cephalosporins, aminoglycosides, andnitorfurantoin; anesthetic agents such as lidocaine, bupivacaine, andropivacaine; anticoagulants such as D-Phe-Pro-Arg chloromethyl ketone,heparin, antithrombin compounds, anti-thrombin antibodies, anti-plateletreceptor antibodies, aspirin, prostaglandin inhibitors, plateletinhibitors; vascular cell growth promoters such as growth factors,growth factor receptor antagonists, transcriptional activators, andtranslational promoters; vascular cell growth inhibitors such as growthfactor inhibitors, growth factor receptor antagonists, transcriptionalrepressors, translational repressors, replication inhibitors, inhibitoryantibodies, antibodies directed against growth factors; andcholesterol-lowering agents.

Examples of suitable biocompatible film-forming agents include, but arenot limited to, synthetic polymers including polyethylen (PE),poly(ethylene terephthalate), polyalkylene terepthalates such aspoly(ethylene terephthalate) (PET), polycarbonates (PC),Polyvinylpyrrolidone (PVP), polyvinyl halides such as polyvinylchloride) (PVC), polyamides (PA), poly(tetrafluoroethylene) (PTFE),poly(methyl methacrylate) (PMMA), polysiloxanes, ethylene-vinyl acetate(EVAc), polyurethane polysiloxanes, and poly(vinylidene fluoride)(PVDF); biodegradable polymers such as poly(glycolide) (PGA),poly(lactide) (PLA) and poly(anhydrides) poly(lactic-co-glycolic acid)(PLGA), PEG-PLA-PEG, PEG-PLGA-PEG, PEG-PCL-PEG, PLA-PEG-PLA, PHB,P(PF-co-EG) ±acrylateend groups, P(PEG/PBO terephthalate),PEG-bis-(PLA-acrylate), PEG6CDs, PEG-g-P(AAm-co-Vamine), PAAm,P(NIPAAm-co-AAc), P(NIPAAm-co-EMA), PVAc/PVA, PNVP, P(MMA-co-HEMA),P(AN-co-allylsulfonate), P(biscarboxy-phenoxy-phosphazene),P(GEMA-sulfate); natural polymers and their derivatives including HA,alginic acid, pectin, carrageenan, chondroitin sulfate, dextrane,sulfate, chitosan, polylysine, collagen, gelatin, carboxymethyl chitin,chitosan, fibrin, collagen, dextran, agarose, pullulan, sclerogluan,cellulose, albumin, silk; and combinations of natural and syntheticpolymers including P(PEG-co-peptides), alginate-g-(PEO-PPO-PEO),P(PLGA-co-serine), collagen-acrylate, alginate-acrylate,P(HPMA-g-peptide), P(HEMA/Matrigel), HA-g-g-NIPAA. Alternatively or inaddition, bio-compatible mineral, vegetable or animal oils may be usedincluding fish oil, cod-liver oil, olive oil, linseed oil, sunfloweroil, corn oil, and/or palm oil.

The solvents used for dissolving the film-forming component and thetherapeutic substance are selected based on their biocompatibility andsolubility of the material to be dissolved. Aqueous solvents can be usedto dissolve water-soluble materials, such as Poly(ethylene glycol) (PEG)and organic solvents may be selected to dissolve hydrophobic and somehydrophilic materials. Examples of suitable solvents include methylenechloride, ethyl acetate, ethanol, methanol, dimethyl formamide (DMF),acetone, acetonitrile, tetrahydrofuran (THF), acetic acid, dimethylesulfoxide (DMSO), toluene, benzene, acids, butanone, water, hexane, andchloroform, N-methylpyrrolidone (NMP), 1,1,2-trichloroethane (TCE),various freons, dioxane, ethyl acetate, cyclohexanone, anddimethylacetamide (DMAC). For the sake of brevity, the term solvent isused to refer to any fluid dispersion medium whether a solvent of asolution or the fluid base of a suspension, as the invention isapplicable in both cases.

The spraying apparatus of the present invention, which is described inmore detail in FIGS. 2 and 3 below, includes a body having at least aliquid conduit extending from a liquid inlet to a liquid orifice and atip for receiving and defining a space for an atomizing gas that may befed through one or more gas inlets. The tip is provided at the atomizingend of the spraying device and surrounds the liquid orifice such that anintermediate space (annular gap) is formed between the body and the tipthrough which an atomizing gas is expelled. The spraying device isdesigned to allow the precise and repeatable machining of the innersurface of the tip, the centering section between tip and body and thetip orifice to ensure optimized concentricity and surface quality of theatomizing end of the spraying device.

While the invention will be described in connection with certainembodiments, it will be understood that the invention is not limited tothese embodiments. On the contrary, the invention includes allalternatives, modifications and equivalents as may be included withinthe spirit and scope of the present invention. Details in theSpecification and Drawings are provided to understand the inventiveprinciples and embodiments described herein, to the extent that would beneeded by one skilled in the art to implement those principles andembodiments in particular applications that are covered by the scope ofthe claims. All dimensions used herein are suggestive and not intendedto be restrictive.

FIG. 1A is a longitudinal cross-sectional view of an exemplary sprayingdevice of the present invention. An expanded view of the atomizing endof the spraying device is provided in FIG. 1B.

The spraying device comprises a body 2 and a tip 3. The body 2 includesa central liquid conduit, which extends from liquid inlet 4 to liquidorifice 15 and gas passages 6 surrounding the fluid conduit in which gasis fed through gas inlets 5. The liquid orifice typically comprises anorifice having a diameter within the range from 0.05 to 0.5 mm. The tip3 is mounted by securing ring 8 to the body 2 and a small annular gap 16is provided to permit passage of gas therethrough from the gas passages6. Tip 3 has typically a tapered inner section 72 having extending toorifice 16. The diameter of the atomizing end of the body and theorifice diameter of the tip define the width of the annulus. To ensurethat the center of the liquid orifice 15 runs coaxial to the center ofthe annular gap 16 there is provided a centering section on the outersurface of the tip to align the tip in relation to the body, as depictedin FIG. 2B by arrow 7. Thus, tip 3 can be easily removed for maintenanceand cleaning without the risk of misalignment between the tip and bodyduring assembling and disassembling.

Alternatively, as shown in FIGS. 2A and 2B the tip of the sprayingdevice may have a centering section 7 on the inner surface of the tip 3.The tip orifice 16, tapered inner section 72 and centering section 7 ofthe tip are substantially concentric to ensure a precise alignmentbetween tip 3 and body 2. The liquid conduit is comprised of a capillarybeing stabilized within the body proximate to the liquid exit, asdescribed in U.S. patent application Ser. No. 11/545,282, to ensure aconstant liquid velocity along the fluid path of the spraying device andto minimize pulsation of the liquid flow. The tapered inner section ofthe tip is designed and manufactured such that a smooth high-precisionsurface is obtained and the error of concentricity between the axis oforifice and axis of inner tapered section is smaller than 20 microns, asdescribed in more detail in FIGS. 3A and 3B below.

The spraying device may also include means to generate a vortical flowof the compressed gas. The body of the spraying device is preferablymade from a metallic material such as stainless steel. Alternatively, apolymeric material such as PEEK can be used. The tip may be made from ametallic material such as stainless steel, titan and the like. The tipmay further comprise additional bores to provide various spray patternssuch as a flat spray.

The spraying device may be connected via liquid inlet 4 to means tosupply the liquid to be atomized, and via gas inlets 5 to means tosupply the atomizing gas (not shown). Typically, the gas used todisintegrate the liquid is chemically inert with respect to the liquidcomponents. Suitable inert gases include, air, nitrogen, and the like.Pressurized air represents an economical atomizing gas, which may besupplied using pressurized tanks or cylinders as well as compressors.The liquid is preferably fed using a high-accuracy syringe pump toensure precise control of the liquid supply.

In operation, the liquid to be atomized is supplied through inlet 4. Theatomizing fluid (compressed gas) is fed into gas inlets 5, travelsthrough gas passages 6 extending from gas inlets 5 via a portionsubstantially coaxial to the liquid line to a conical portion defined bythe tip 3 and exits the atomizer trough annular gap 16. The liquid flowsfrom liquid inlet port 4 through the liquid conduit to the atomizing endand is disintegrated into fine droplets by the atomizing gas outside thespraying device upon exiting orifice 15.

It may be desirable to furthermore provide electrostatic means to assistthe liquid disintegration process. A high voltage source can beelectrically connected to the liquid conduit of the spraying devicewhile portions of the spraying devices are electrically isolated fromthe liquid conduit.

The present invention is particularly useful when mixing multipleliquids, since the quality of the tip of the spraying device is crucialfor a uniform velocity distribution around the angular gap and areproducible liquid disintegration and mixing process. In an alternativeembodiment, the spraying may comprise an additional liquid inletextending to a second liquid conduit to feed a second liquid separatelyto a second liquid orifice surrounding the first liquid orifice. Anadditional annular gap is provided between the body and the secondorifice. The tip of the spraying device is designed and manufacturedsuch that an optimized concentricity and surface quality as well asalignment to the liquid orifice are provided. The spraying apparatus ispreferably connected to means to separately supply either simultaneouslyor consecutively at least two liquids, such as a composition comprisinga polymeric component and a composition comprising a therapeutic agent,and an atomizing gas. In operation, a first liquid may be fed into thefirst liquid conduit and directed to the first orifice and a secondliquid into second liquid conduit and directed to the second orifice.The atomizing gas may be supplied to one or more gas inlets, directedthrough passages to the gas orifice and discharged through the gasorifice with an equal velocity distribution around the gas annulus. Thefirst and second liquids are disintegrated and homogeneously mixed bythe aerodynamic forces upon exiting the liquid orifices and a fine sprayis obtained.

In order to improve the spray performance and reproducibility beneathindividual spraying devices and to assure a reproducible quality withina plurality of devices of the same type, a manufacturing procedure formachining the atomizing end of the spraying device has been developed.

The manufacturing procedure of the tip of the spraying device, which isschematically visualized in FIGS. 3A and 3B, consists in drilling a borehaving a diameter smaller than the diameter of the finished orifice andmachining tip orifice 16, inner surface 72 and centering section 35 inone setting. Tip orifice 16 and inner surface of the tip are preferablymachined by internal turning and centering section 35 by externalturning. Alternatively, the inner surface of the tip and the orifice maybe bored out or grinded.

The manufacturing procedure of the tip of the spraying device, which isschematically visualized in FIGS. 3A and 3B, consists in drilling a borehaving a diameter smaller than the diameter of the finished orifice andmachining tip orifice 16 and at least a portion of the inner surface 72and preferably centering section 7 to minimize the error ofconcentricity between orifice 16 and inner surface 72. The machiningoperations are preferably performed in the same setting. In oneembodiment the tip orifice 16 and the inner surface of the tip arepreferably machined by internal turning and centering section 7 byexternal turning. Alternatively, the inner surface of the tip and theorifice may be bored out or grinded.

As shown in FIG. 3B, a small bore tool 75 having cutting edge 74 may bemoved along the final machining path illustrated by line 73. Themachining path extends from the tapered inner section of the tip toorifice 16 such that a smooth transition between tapered section andorifice is ensured. By machining the inner surface of the tip 72including the tip orifice in one setup an improved concentricity,roundness and smooth finish of tip inner surface and orifice as well asannular gap is obtained. The centering section 7 may preferably at leastpartially manufactured in the same setup as shown by machining path 76.By manufacturing the final shape of the orifice, the inner surface ofthe tip and the centering section in the same setup an improvedconcentricity is obtained resulting in a optimized alignment betweenbody orifice 15 and tip 3 orifice.

Thus, the concentricity between the axis of body orifice 15 and the axisof orifice 16 of tip 3 is substantially improved compared to prior artatomizers. In addition, a repeatable and cost-effective manufacturingmethod of the tip of the spraying device which is crucial for the sprayperformance of the spraying apparatus is provided resulting in improvedaccuracy of the spraying device compared to conventional machiningmethods based on machining the tip in several setups.

In order to demonstrate the spray quality of the spraying device of thepresent invention as well as the spray performance of several sprayingdevices within a series with respect to prior art devices, various spraytests have been conducted as described below.

Droplet Size Consistency Comparison

To compare the performance of the spraying device of the presentinvention in terms of atomization consistency over time a droplet sizeanalysis has been conducted.

The spray performance of the spraying device of the present inventionshown in FIG. 2 with an orifice diameter of 0.8 mm has been compared toa prior art spraying device having an orifice diameter of 1.1 mm. Theprior art spraying device has been inspected using a microscope and SEMto ensure that the annular gap has a homogeneous width and the orificeshave an optimum concentricity and roundness. Thus, the prior artspraying device meets known quality criteria and is expected to producea stable and homogenous spray.

A Laser Diffractometer (Sympatec, Lawrenceville, N.J.) which was located30 mm downstream from the orifice of the spraying devices was used tomeasure the droplet distributions. A polymer solution comprising of 11mg/ml PBMA dissolved in THF was supplied by a syringe pump (HamiltonCompany, Reno, Nev.) at a flow rate of 15 ml/h to the liquid inlet ofthe spraying device. The atomizing gas was fed at a flow rate of 8 l/mininto the gas inlet. Ten measurement runs have been conducted with aduration of 10 seconds per run.

Referring to FIG. 6, ten measurements of the droplet size distributionsare shown for both the spraying device of the present invention and ofthe prior art. It can be seen, that the droplets generated by the priorart atomizing device have an inconsistent size compared to the sprayingdevice of the present invention.

Furthermore, the coefficient of variation (COV) has been calculated forthe ×10, ×50, ×90, ×99 and the volume median diameter (VMD) value asshown in Tables 1 and 2 below.

TABLE 1 PRIOR ART Droplet size measurement of one spraying device during10 meas. runs Meas. ×10 [μm] ×50 [μm] ×90 [μm] ×99 [μm] VMD [μm] 1 1.468.29 16.93 25.8 8.82 2 1.45 8.21 16.81 25.44 8.73 3 1.45 8.14 16.7525.41 8.67 4 1.47 8.22 17.11 28.24 8.88 5 1.47 8.28 17.15 28.17 8.92 61.48 7.92 17.10 28.20 8.68 7 1.46 8.18 17.09 28.46 8.89 8 1.46 8.2017.12 28.47 8.91 9 1.46 8.20 17.1 28.16 8.85 10  1.45 8.27 17.43 32.999.13 Mean 1.46 8.19 17.06 27.93 8.85 COV [%] 0.7 1.3 1.1 7.9 1.5

TABLE 2 INVENTION Droplet size measurement of one spraying device during10 meas. runs Meas. ×10 [μm] ×50 [μm] ×90 [μm] ×99 [μm] VMD [μm] 1 0.764.21 8.51 12.47 4.36 2 0.76 4.20 8.50 12.46 4.36 3 0.76 4.21 8.52 12.464.37 4 0.76 4.21 8.52 12.47 4.37 5 0.76 4.21 8.51 12.45 4.36 6 0.76 4.218.52 12.46 4.37 7 0.76 4.21 8.52 12.47 4.37 8 0.76 4.21 8.52 12.48 4.379 0.76 4.22 8.53 12.47 4.37 10  0.76 4.20 8.52 12.48 4.36 Mean 0.76 4.218.52 12.47 4.37 COV [%] 0.0 0.1 0.1 0.1 0.1

FIG. 7 illustrates the coefficient of variation of ten droplet sizemeasurements of both the spraying device of the present invention andfor the prior art spraying device. The droplet size variation over timeof the prior art spraying device is 0.7% for the ×10 value and 1.3% forthe ×50 value and 7.9% for the ×99 value. In contrast, the sprayingdevice of the current invention generates droplets having a consistentsize during the entire spray run that are significantly smaller than thevalues obtained for the prior art spraying device, resulting in adroplet size variation between 0% and 0.1%.

Droplet Size Variation Comparison

Droplet size distribution measurements for ten individual sprayingdevices for both the spraying device of the present invention and of theprior art have been conducted as described below.

Ten individual spraying devices of the present invention shown in FIG. 3having an orifice diameter of 1.1 mm have been compared to tenindividual prior art spraying device having an orifice diameter of 1.1mm. The prior art spraying devices have been inspected using amicroscope and SEM to ensure that the annular gap has a homogeneouswidth and the orifices have an optimum concentricity and roundness.Thus, the prior art spraying devices meet known quality criteria and areexpected to produce a stable and homogenous spray.

A droplet size analysis has been performed using a Laser Diffractometer(Sympatec, Lawrenceville, N.J.), which was located 30 mm downstream fromthe orifice of the spraying devices. Deionized water was supplied by asyringe pump (Hamilton Company, Reno, Nev.) at a flow rate of 15 ml/hand the atomizing gas was fed at a flow rate of 8 l/min into the gasconduit of the atomizer.

FIG. 8 depicts ten individually measured droplet size distributions often prior art spraying devices and FIG. 9 ten individually measureddroplet size distributions of ten spraying devices of the presentinvention. It can be seen, that there large performance deviationsbetween the prior art devices. In contrast, the spraying devices of thepresent invention produce a consistent spray performance.

To quantify the performance deviations between the atomizers thecoefficient of variation (COV) has been calculated for the ×10, ×50,×90, ×99 and for the VMD value as shown in the Tables 3 and 4 below.

TABLE 3 PRIOR ART Droplet size measurement of 10 individual sprayingdevices Device ×10 [μm] ×50 [μm] ×90 [μm] ×99 [μm] VMD [μm] 1 2.50 11.9823.61 46.65 13.06 2 1.99 10.01 20.10 31.80 10.82 3 2.53 11.90 22.0933.68 12.35 4 2.72 13.01 23.99 35.29 13.41 5 2.31 11.80 20.71 31.5111.97 6 3.35 12.85 20.68 30.54 12.75 7 2.26 11.17 22.99 40.71 12.31 82.13 10.70 21.14 35.22 11.54 9 2.40 11.65 22.88 37.09 12.47 10  2.2311.10 21.88 35.81 11.93 Mean 2.44 11.62 22.01 35.83 12.26 COV [%] 15.67.9 6.1 13.5 6.1

TABLE 4 INVENTION Droplet size measurement of 10 individual sprayingdevices Device ×10 [μm] ×50 [μm] ×90 [μm] ×99 [μm] VMD [μm] 1 2.69 12.4224.17 36.74 13.20 2 2.57 12.13 23.37 35.68 12.80 3 2.70 12.66 24.2737.22 13.35 4 3.02 12.18 22.72 36.13 12.82 5 2.58 11.99 23.38 35.5912.73 6 2.83 12.76 24.22 36.81 13.40 7 2.64 12.09 23.85 36.38 12.93 82.67 12.30 23.99 36.22 13.08 9 2.51 11.99 23.68 35.97 12.81 10  2.5512.07 23.92 36.33 12.92 Mean 2.68 12.26 23.76 36.31 13.00 COV [%] 5.72.2 2.0 1.4 1.9

As shown in FIG. 10, the variation between the ten prior art sprayingdevices is 15.6% for the ×10 value, 7.9% for the ×50 value and 13.5% forthe ×99 value and the variation between the ten spraying devices of thepresent invention is 5.7% for the ×10 value, 2.2% for the ×50 value and1.9% for the ×99 value. It can be seen that the performance deviationsbetween the spraying devices of the present invention are significantlysmaller than the performance deviations between the prior art sprayingdevices.

The results of the spray tests described above outline the advantages ofthe design and manufacturing methodology adopted for the spraying deviceof the present invention in terms of droplet size and droplet sizeconsistency during several spray runs and performance consistencybetween several spraying devices.

The prior art devices showed a poor performance and considerableperformance deviation despite having a high quality atomizing end(annular gap with a homogeneous width about the perimeter and orificeswith an optimum concentricity and roundness).

It has been demonstrated that the spray performance is considerablyaffected by an error in concentricity between the axis of the innersection of the tip and the axis of the tip orifice. FIG. 4 is aschematic representation of an exemplary error in concentricityresulting in an eccentricity between axis 71 of inner tapered section 72and axis 70 of tip orifice 16.

To visualize the impact of the concentricity between the inner taperedsurface of the tip and the tip orifice on a stent coating process,several computational fluid dynamics (CFD) simulations have beenperformed. FIG. 5 shows an inhomogeneous gas velocity within the annulargap resulting from an error in concentricity of the tip, which may leadas shown in FIG. 12 to a nebulization of the liquid composition by theatomizing gas that is inhomogeneous on different sides of the sprayplume.

FIGS. 11 and 12 show the droplet trajectories with respect to the stentto be coated. The axis of the stent and the axis of the spraying devicewere located on the same plane at a distance of 14 mm downstream fromthe nozzle and the droplet trajectories were calculated for dropletshaving a diameter of 10 microns. Referring to FIG. 11, a model of thespraying apparatus of the present invention as shown in FIG. 3 and asubstantially concentric alignment and a minimized error ofconcentricity between inner tapered section of tip and tip orifice isdepicted. It can be seen, that the atomizing gas exits the gas orifice16 and transports the droplets that are discharged from the liquidorifice to the stent 54 so that the droplet trajectories are uniformlydistributed around the extended longitudinal axis of the spraying deviceresulting in a homogeneous droplet distribution in relation to the stent54. This is due to the uniform velocity distribution of the atomizinggas about the perimeter of the annulus, which is the presumption forreproducible homogeneous coatings. FIG. 12 represents a model of theprior art spraying apparatus having an annular gap with a constant widthand a small error of concentricity between inner tapered section of thetip and the tip orifice of about 20 microns. Due to the inhomogeneousgas velocities about the perimeter of the gas annulus 16 the droplettransport process is disturbed and the droplet trajectories are shiftedin relation to the axis of the spraying device resulting in aninhomogeneous droplet distribution in relation to stent 54. It has beendemonstrated that small imperfections of the tip have a considerableimpact on the droplet disintegration and transportation process and willresult in overspray (droplets don't reach spray target) andinhomogeneous coatings (stent is not homogeneously covered by droplet)leading to coating weight deviations and an inhomogeneous distributionof the therapeutic substance.

Thus, small imperfections of the tip have a considerable impact on thedroplet disintegration and transportation process and will result inoverspray (droplets don't reach spray target) and inhomogeneous coatings(stent is not homogeneously covered by droplet) which may result incoating weight deviations and an inhomogeneous distribution of thetherapeutic substance used un the specific drug delivery application.

The following example has been provided to illustrate the advantages ofthe present invention in a stent coating application. Stents are tiny,expandable mesh tubes supporting the inner walls of a lumen used torestore adequate blood flow to the heart and other organs that werecoated according to the method of the present invention.

Stent Coating Example

Multiple stents having a diameter of 2 mm and a length of 20 mm wereinspected using a microscope and weighted with a microbalance beforeapplying a coating composition comprising a polymer and a therapeuticagent to obtain a target coating weight of 320 μg as described below.

The stents were mounted on a holding device as described in U.S. Pat.App. No. 60/776,522 incorporated herein as a reference. The sprayingdevice of FIG. 4 was used to disintegrate the coating composition intofine droplets and apply the coating to the stents.

For best results, the spraying device may be aligned in relation to thestent so that the spray axis of the atomizer is perpendicular to therotation axis of the stent and both axes are in the same plane. Theorifice of the spraying device is preferably positioned at a distance ofapproximately 12 to 35 mm from the outer surface of the stent.

The liquid inlet of the spraying device is connected to a liquid supplysource. A syringe pump (Hamilton Inc., Reno, Nev.) is preferably used tofeed the coating composition to the spraying device. The compressed gasis fed into the spraying device. The gas flow rate may range between 3and 10 l/min and the flow rate of the coating solution may be in theorder of 0.5 ml/h to 50 ml/h. The spraying device can disintegrate thecoating solution into fine droplets.

The liquid is supplied to the liquid conduit of the spraying devicehaving a constant diameter and the liquid is directed at a constantliquid velocity from the liquid inlet to the liquid orifice. The gas isfed into the gas conduit and flows through a tapered section to the gasannulus and a homogeneous gas velocity is produced about the perimeterof the annular gap. The expelled gas stream impinges on the liquidemerging from the liquid orifice and disintegrates the liquid into finedroplets.

The spraying process may be monitored using an optical patternator inorder to ensure that the spatial droplet distribution of the generatedspray plume is in the desired limits as described in U.S. Pat. App. No.60/674,005 incorporated by reference herein.

During the application of the coating solution, rotary motion istransmitted to the stent to rotate the stent about its centrallongitudinal axis. The rotation speed can be from about 5 rpm to about250 rpm. By way of example, the stent may rotate at 130 rpm. The stentis translated along its central longitudinal axis along the atomizer.The translation speed of the stent can be from about 0.2 mm/s to 8 mm/s.When applying the coating solution, the translation speed is preferably0.5 mm/s. The stent can be moved along the atomizer one time to applythe coating in one pass or several times to apply the coating in severalpasses. Alternatively, the atomizer may be moved one time or severaltimes along the stent length.

After application of the coating, the coated stents were inspected andweighted to determine the coating weight. The coefficient of variationof the coating weight was only 1.4% which outlines the superiorperformance and accuracy of the spraying device of the presentinvention.

It has been demonstrated, that using the spraying device of the presentinvention a stable coating process is obtained resulting in homogeneoushigh-accuracy coatings with a reproducible coating weight.

The stent coating example outlines the impact of the spraycharacteristics of the spraying device on the coating quality andreproducibility. Deviations of the quantity and of the distribution ofthe therapeutic agent in the coating, which may have a negative impacton the particular drug delivery application, can be therefore prevented.

1. A device to disintegrate a liquid into fine droplets using anatomizing gas comprising a body having at least a liquid conduitextending from a liquid inlet to a liquid orifice and a tip defining aspace for receiving the atomizing gas and having an inner taperedsection extending to an orifice wherein the tip is essentially coaxialwith the body and an annular gap through which the atomizing gas isexpelled is formed between the body and the orifice of the tip and atleast the orifice of the tip and a portion of the inner tapered sectionof the tip are machined to minimize the error of concentricitytherebetween so that during operation a gas stream with a substantiallyuniform gas velocity distribution about the perimeter of the annular gapis formed.
 2. The device according to claim 1, wherein the orifice ofthe tip has a diameter of less than 1.2 mm and the error ofconcentricity between the orifice and said portion of the inner taperedsection is less than 20 microns.
 3. The device according to claim 1,wherein at least said portion of the inner section of the tip ismachined in the same setup as the orifice of the tip.
 4. The deviceaccording to claim 1, wherein the tip is machined by a turningoperation.
 5. The device according to claim 1, wherein the tip furthercomprises a centering section to align the tip in relation to the bodyand the error of concentricity between the orifice of the tip and thecentering section is smaller than 20 microns.
 6. The device according toclaim 5, wherein the centering section is machined in the same setup asthe orifice of the tip.
 7. The device according to claim 1, wherein theliquid conduit is free of constrictions.
 8. The device according toclaim 7, wherein the liquid conduit is comprised of a capillary.
 9. Thedevice according to claim 1, further comprising a second liquid inletextending to a second liquid orifice surrounding and being essentiallycoaxial with the first liquid orifice to separately supply a secondliquid, wherein the second liquid is disintegrated by the atomizing gasupon exiting the second liquid orifice and mixed with the first liquid.10. The device according to claim 1, further comprising electrostaticmeans to atomize the liquid.
 11. (canceled)
 12. (canceled) 13.(canceled)
 14. (canceled)
 15. Method to apply a coating to a medicaldevice using a spraying device having a body with a liquid conduitextending from a liquid inlet to a liquid orifice and a tip beingessentially coaxial with the body and defining a space for receiving anatomizing gas, the tip having an inner section extending to an orificewith a diameter of less than 1.2 mm for discharging the atomizing gasthrough an annular gap formed between the body and the orifice of thetip, comprising the following steps: feeding a liquid into the liquidconduit and feeding a gas into the gas conduit and forming a gas streamhaving a substantially uniform gas velocity distribution about theperimeter of the annular gap; disintegrating the liquid into finedroplets through the momentum of the gas emerging from the annular gap;directing the droplets within the gas stream to the medical device sothat the droplet trajectories are uniformly distributed around theextended longitudinal axis of the spraying device; and forming a coatingon the medical device.
 16. The method of claim 15, wherein the error ofconcentricity between the inner section of the tip and the orifice ofthe tip is less than 20 microns.
 17. The method of claim 15, wherein thevolume median diameter of the generated droplets is less than 10microns.
 18. The method of claim 15, wherein the liquid flow is directedat a substantially constant velocity from the liquid inlet to the liquidorifice.
 19. The method of claim 15, wherein the droplet size variationis less than 1%.
 20. (canceled)
 21. The method of claim 15, wherein theliquid comprises a polymeric component.
 22. The method of claim 15,further comprising the step of feeding a second liquid through anadditional orifice positioned between the first liquid orifice and theorifice for the atomizing gas and disintegrating and mixing the secondliquid with the first liquid through the momentum of the atomizing gasemerging from the annular gap.
 23. Method to form a reproducible coatingon multiple stents using multiple spraying devices comprising thefollowing steps: providing multiple stents; providing multiple sprayingdevices having a body with at least a liquid orifice and a tip beingessentially coaxial with the body and defining a space for receiving anatomizing gas, the tip having an inner section extending to an orificefor discharging the atomizing gas through an annular gap formed betweenthe body and the orifice of the tip; feeding a liquid into each sprayingdevice and feeding a gas into each spraying device and forming a gasstream with a substantially uniform gas velocity distribution about theperimeter of the annular gap; disintegrating the liquid into finedroplets through the momentum of the gas emerging from the annular gapso that the variation of the volume median diameter of the spraysproduced by the separate spraying devices is less than 2%; directing thedroplets within the gas streams to the medical devices so that thedroplet trajectories are uniformly distributed around the extendedlongitudinal axis of the spraying device; and forming a coating on thestents.
 24. The method of claim 23, wherein the orifice of the tip has adiameter of less than 1.2 mm and the error of concentricity between theinner section of the tip and the orifice of the tip is less than 20microns.
 25. The method of claim 23, wherein the error of concentricitybetween the inner section and the orifice of the tip is less than 1.7%of the orifice diameter of the tip.